ABSTRACT
The Decoy Receptor 3 (DcR3) is known to compete with the signalling receptors of the Fas ligand (FasL), LIGHT and the TNF-like molecule 1A (TL1A). The primary aim of this study was to provide insights into the role of DcR3 in the modulation of myelin-specific encephalitogenic autoimmune T cell responses. Treatment of PLP-specific lymph node cells with DcR3.Fc protein resulted in a suppression of IFN-g and IL-17, in a reduced proportion of Th17 cells and in a decrease of encephalitogenicity. The Th17 response promoting cytokines IL-6 and IL-23 were suppressed by DcR3.Fc as well. DcR3.Fc-treatment of CD4+ T cells with a defective FasL did not influence the production of IL-17 indicating that DcR3 suppresses IL-17 production by disruption of Fas-FasL interactions. We identified high concentrations of DcR3 in the cerebrospinal fluid (CSF) of patients with various neurological disease states while almost no DcR3 was detected in corresponding serum samples. In conclusion, DcR3 modulates CNS-autoimmunity by interfering with Th17 responses via blockade of Fas-FasL interaction. The anti-inflammatory properties and high DcR3 concentrations in the CSF warrant further investigations in the expression pattern and the function of DcR3 within the CNS.
Subject(s)
Encephalitis/cerebrospinal fluid , Encephalitis/immunology , Encephalomyelitis, Autoimmune, Experimental/cerebrospinal fluid , Encephalomyelitis, Autoimmune, Experimental/immunology , Immune Tolerance/immunology , Receptors, Tumor Necrosis Factor, Member 6b/cerebrospinal fluid , Animals , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/immunology , Disease Models, Animal , Encephalitis/physiopathology , Encephalomyelitis, Autoimmune, Experimental/physiopathology , Fas Ligand Protein/drug effects , Fas Ligand Protein/metabolism , Female , Humans , Interferon-gamma/drug effects , Interferon-gamma/metabolism , Interleukin-17/metabolism , Interleukin-23/metabolism , Interleukin-6/metabolism , Mice , Mice, Inbred C57BL , Mice, Mutant Strains , Receptors, Tumor Necrosis Factor, Member 6b/pharmacology , Recombinant Fusion Proteins/pharmacology , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , fas Receptor/drug effects , fas Receptor/metabolismABSTRACT
Adiponectin circulates in the body in high concentrations, and 100-fold lower amounts were described in the cerebrospinal fluid (CSF) of mice, whereas in humans, contradictory results have been published. To clarify whether adiponectin is present in human CSF and is derived from the circulation, it was determined in human CSF and plasma of 52 nonselected patients. Adiponectin was detected by immunoblot in CSF and was quantified in CSF and serum by ELISA. CSF adiponectin was positively correlated to systemic levels, and the CSF/serum adiponectin ratio was correlated to the CSF/serum albumin ratio. Furthermore, disturbed function of the blood-brain barrier (BBB) was associated with an elevated CSF/serum adiponectin ratio. Adiponectin mRNA was not found in the brain, indicating that adiponectin crosses the BBB and/or the blood-cerebrospinal fluid barrier (BCB). Rat adiponectin with a COOH-terminal tag was injected into the tail vein of rats and was detected 3 h later in CSF. However, CSF adiponectin in humans and rats was approximately 0.1% of the serum concentration and therefore was below the 0.5% expected in the CSF because of the residual leakage of an undisturbed BBB/BCB. Taken together, data from the present study show that adiponectin in human CSF is far below the level expected by the baseline BBB/BCB permeability, indicating that adiponectin enters the brain much less efficiently than albumin, thus supporting recent data that exclude adiponectin transport to the CSF. Additional studies are needed to reveal whether these low levels of adiponectin in CSF have a physiological function.
